William Perkins

Interventions for basal cell carcinoma of the skin: systematic review

Abstract Objectives To assess the effects of treatments for basal cell carcinoma. Methods Systematic review of randomised controlled trials. Main outcome measure Recurrence of basal cell carcinoma at three years or beyond, assessed clinically. Studies reviewed Randomised controlled trials of interventions for histologically confirmed basal cell carcinoma (published and unpublished material; no language restrictions). Results 25 studies were identified, covering seven therapeutic categories. Only one study of surgical excision versus radiotherapy contained primary outcome data, which showed significantly more persistent tumours and recurrences in the radiotherapy group compared with surgery (odds ratio 0.09, 95% confidence interval 0.01 to 0.67). One study compared cryotherapy with surgery, with inconclusive results at one year. In a comparison of radiotherapy with cryotherapy, significantly more recurrences occurred at one year in the cryotherapy group. Preliminary studies suggest a short term success rate of 87-88% for imiquimod cream in the treatment of superficial basal cell carcinoma, although this cream has not been compared with surgery. No consistent evidence was found for the other treatment modalities. Conclusions Little good quality research has been done on the treatments used for the most common cancer in humans. Most trials have included only people with basal cell carcinoma occurring at low risk sites. Only one trial measured recurrence at four years; recurrence rates at one year should be interpreted with caution. Surgery and radiotherapy seem to be the most effective treatments; surgery showed the lowest failure rates. Other treatments might have some use but need to be compared with surgery.

Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy.

Significance Histopathology is the standard method for diagnosis of cancer. However, this method requires time-consuming procedures for sectioning and staining of tissues, making histopathology impractical for use during surgery for most cancer types. We report a unique method based on two optical spectroscopy techniques—autofluorescence imaging and Raman scattering—that can accurately measure molecular differences between tumor cells and healthy tissue and allows diagnosis of tumors faster than histopathology, without requiring tissue sectioning or staining. Our study demonstrates the potential of this technique for diagnosis of tissues during cancer surgery, providing a quick and objective way to determine whether the tissue layers removed by the surgeon are clear of tumor. Tissue-conserving surgery is used increasingly in cancer treatment. However, one of the main challenges in this type of surgery is the detection of tumor margins. Histopathology based on tissue sectioning and staining has been the gold standard for cancer diagnosis for more than a century. However, its use during tissue-conserving surgery is limited by time-consuming tissue preparation steps (1–2 h) and the diagnostic variability inherent in subjective image interpretation. Here, we demonstrate an integrated optical technique based on tissue autofluorescence imaging (high sensitivity and high speed but low specificity) and Raman scattering (high sensitivity and high specificity but low speed) that can overcome these limitations. Automated segmentation of autofluorescence images was used to select and prioritize the sampling points for Raman spectroscopy, which then was used to establish the diagnosis based on a spectral classification model (100% sensitivity, 92% specificity per spectrum). This automated sampling strategy allowed objective diagnosis of basal cell carcinoma in skin tissue samples excised during Mohs micrographic surgery faster than frozen section histopathology, and one or two orders of magnitude faster than previous techniques based on infrared or Raman microscopy. We also show that this technique can diagnose the presence or absence of tumors in unsectioned tissue layers, thus eliminating the need for tissue sectioning. This study demonstrates the potential of this technique to provide a rapid and objective intraoperative method to spare healthy tissue and reduce unnecessary surgery by determining whether tumor cells have been removed.

Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.

Objectives To assess the effects of treatments for non-metastatic invasive squamous cell carcinoma (SCC) of the skin using evidence from observational studies, given the paucity of evidence from randomised controlled trials. Design Systematic review of observational studies. Data sources Medline, Embase, to December 2012. Review methods Observational studies of interventions for primary, non-metastatic, invasive, SCC of the skin that reported recurrence during follow-up, quality of life, initial response to treatment, adverse events, cosmetic appearance, or death from disease. Studies were excluded if data for primary cutaneous SCC was not separable from other data. Data were extracted independently by two reviewers. Meta-analysis was performed where appropriate using a random effects model to estimate the pooled proportion of an event with 95% confidence intervals. Results 118 publications were included, covering seven treatment modalities. Pooled estimates of recurrence of SCCs were lowest after cryotherapy (0.8% (95% confidence interval 0.1% to 2%)) and curettage and electrodesiccation (1.7% (0.5% to 3.4%)), but most treated SCCs were small, low risk lesions. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods from 10 studies was 3.0% (2.2% to 3.9%), which was non-significantly lower than the pooled average local recurrence of 5.4% (2.5% to 9.1%) after standard surgical excision (12 studies), and 6.4% (3.0% to 11.0%) after external radiotherapy (7 studies). After an apparently successful initial response of SCCs to photodynamic therapy, pooled average recurrence of 26.4% (12.3% to 43.7%; 8 studies) was significantly higher than other treatments. Evidence was limited for laser treatment (1 study) and for topical and systemic treatments (mostly single case reports or small non-comparative series with limited follow-up). Conclusions Many observational studies have looked at different treatment modalities for SCC, but the evidence base for the effectiveness of these interventions is poor. Comparison of outcomes after different treatments should be interpreted cautiously owing to biases inherent in the types of study included, and lack of direct comparisons to enable the estimation of relative treatment effect. Further evidence is needed to develop a prognostic model and stratify individuals at high risk of developing SCC, to improve the evidence base for this common cancer and to optimise clinical management. Protocol registration International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD42011001450.

Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial

BACKGROUND Basal-cell carcinoma is the most common form of skin cancer and its incidence is increasing worldwide. We aimed to assess the effectiveness of imiquimod cream versus surgical excision in patients with low-risk basal-cell carcinoma. METHODS We did a multicentre, parallel-group, pragmatic, non-inferiority, randomised controlled trial at 12 centres in the UK, in which patients were recruited between June 19, 2003, and Feb 22, 2007, with 3 year follow-up from June 26, 2006, to May 26, 2010. Participants of any age were eligible if they had histologically confirmed primary nodular or superficial basal-cell carcinoma at low-risk sites. We excluded patients with morphoeic or recurrent basal-cell carcinoma and those with Gorlin syndrome. Participants were randomly assigned (1:1) via computer-generated blocked randomisation, stratified by centre and tumour type, to receive either imiquimod 5% cream once daily for 6 weeks (superficial) or 12 weeks (nodular), or surgical excision with a 4 mm margin. The randomisation sequence was concealed from study investigators. Because of the nature of the interventions, masking of participants was not possible and masking of outcome assessors was only partly possible. The trial statistician was masked to allocation until all analyses had been done. The primary outcome was the proportion of participants with clinical success, defined as absence of initial treatment failure or signs of recurrence at 3 years from start of treatment. We used a prespecified non-inferiority margin of a relative risk (RR) of 0.87. Analysis was by a modified intention-to-treat population and per protocol. This study is registered as an International Standard Randomised Controlled Trial (ISRCTN48755084), and with ClinicalTrials.gov, number NCT00066872. FINDINGS 501 participants were randomly assigned to the imiquimod group (n=254) or the surgical excision group (n=247). At year 3, 401 (80%) patients were included in the modified intention-to-treat group. At 3 years, 178 (84%) of 213 participants in the imiquimod group were treated successfully compared with 185 (98%) of 188 participants in the surgery group (RR 0.84, 98% CI 0.78-0.91; p<0.0001). No clear difference was noted between groups in patient-assessed cosmetic outcomes. The most common adverse events were itching (211 patients in the imiquimod group vs 129 in the surgery group) and weeping (160 vs 81). We recorded serious adverse events in 99 (40%) of 249 participants in the imiquimod group and 97 (42%) of 229 in the surgery group had serious adverse events, but none were regarded as related to treatment. 12 (5%) participants in the imiquimod group withdrew because of adverse events compared with four (2%) in the surgery group. INTERPRETATION Imiquimod was inferior to surgery according to our predefined non-inferiority criterion. Although excisional surgery remains the best treatment for low-risk basal-cell carcinoma, imiquimod cream might still be a useful treatment option for small low-risk superficial or nodular basal-cell carcinoma dependent on factors such as patient preference, size and site of the lesion, and whether the patient has more than one lesion. FUNDING Cancer Research UK.

Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging

A method is presented for acquiring high-spatial-resolution spectral maps, in particular for Raman micro-spectroscopy (RMS), by selectively sampling the spatial features of interest and interpolating the results. This method achieves up to 30 times reduction in the sampling time compared to raster-scanning, the resulting images have excellent correlation with conventional histopathological staining, and are achieved with sufficient spectral signal-to-noise ratio to identify individual tissue structures. The benefits of this selective sampling method are not limited to tissue imaging however; it is expected that the method may be applied to other techniques which employ point-by-point mapping of large substrates.

Mohs micrographic surgery for dermatofibrosarcoma protuberans (DFSP): A single-centre series of 76 patients treated by frozen-section Mohs micrographic surgery with a review of the literature

Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade sarcoma that typically presents with local invasion but rarely metastasises. Surgical excision remains the first-line treatment for DFSP. There are no randomised controlled or prospective studies comparing wide local excision (WLE) with Mohs micrographic surgery (MMS), but available evidence from the retrospective studies and case series available has consistently shown higher recurrence rates for standard surgery and WLE than for MMS. Combined recurrence rates of data within the last 20 years for WLE have been reported at 7.3% compared with 1.1% for MMS. Our aim was to review the clinical details and recurrence rates of DFSP cases treated with frozen-section MMS in our centre between 1996 and February 2013. The relevant data were collected from the case notes. It involved 76 patients with nine of these patients lost to follow-up. In the remaining 67 (67/76) cases, the recurrence rate was 1.5% during the mean follow-up period of 50 months (2-132). This is comparable to recurrence rates for the MMS in the literature [20,21]. Our series is the largest series for frozen-section MMS reported to date. Based on these findings and the current literature evidence, we advocate MMS as the treatment of choice for DFSP in all locations.

Heterozygous Mutations in AAGAB Cause Type 1 Punctate Palmoplantar Keratoderma with Evidence for Increased Growth Factor Signaling

TO THE EDITOR Punctate palmoplantar keratoderma (punctate PPK or PPKP) is a rare autosomal dominant disorder of keratinization. Three variants of this disease have been described; PPKP1 (OMIM ♯148600, Buschke–Fischer–Brauer type) is characterized by the progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin. Linkage analyses of families affected by PPKP1 have previously identified a locus within 15q22–q24 (Martinez-Mir et al., 2003; Gao et al., 2005), but two Chinese pedigrees with a PPKP1 phenotype demonstrated linkage on chromosome 8q24.13–q24.21 (Zhang et al., 2004). Recently, nonsense mutations in AAGAB, the gene encoding alpha- and gamma-adaptin-binding protein p34, were reported in three PPKP1 families (Giehl et al., 2012). Simultaneously, we applied whole-exome sequencing and reported heterozygous loss-of-function mutations in AAGAB in 18 PPKP1 kindreds (Pohler et al., 2012). AAGAB is located on chromosome 15q22, within one of the previously reported linkage regions (Martinez-Mir et al., 2003; Pohler et al., 2012). We now report the AAGAB genotype in a further 12 PPKP1 patients from 6 independent kindreds of Scottish, English, and Mexican ancestry. This study was carried out in accordance with the Declaration of Helsinki Principles, and all subjects gave written informed consent.

Erosive pustular dermatosis: new description of a possible cause of the non-healing burn wound.

INTRODUCTION Erosive pustular dermatosis (EPD) is a cutaneous condition, characterised by sterile pustular lesions, erosions and crusting. Extensive or infected disease may result in scarring. EPD has never been reported following burn. The aim of this study was to describe the presentation and management of EPD complicating burns wounds. METHODS A consecutive series of EPD cases secondary to burn. RESULTS Six cases were identified. In each case, erosive lesions and crusts were located at the site of burn or at the site of split skin grafting after tangential burn excision. All cases presented as failure to heal or repeated wound breakdown, despite standard burn wound management. Pain was a significant feature in all cases. Microbiological cultures demonstrated either benign colonising bacteria or no pathogens. Time to EPD diagnosis by the interdisciplinary team was 126 ± 27 days (mean ± SEM). Topical therapy with short course, potent corticosteroids resulted in clinical remission in 15 ± 2 days (mean ± SEM) without clinical relapses after 15 ± 4 months (mean ± SEM). CONCLUSION EPD may occur following burns. EPD should be considered in the differential diagnosis of a non-healing burn wound and resolves readily with topical potent corticosteroid therapy.

Johnson square procedure for lentigo maligna and lentigo maligna melanoma.

Lentigo maligna (LM) and lentigo maligna melanoma (LMM) can be difficult to manage surgically. Predetermined margins can be inadequate because of subclinical spread, or can affect function when margins are adjacent to the eye or mouth.

Extraordinary reticulate hyperpigmentation occurring after Bier block

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